We seek to advance the understanding of the physiology and pathophysiology of the hypothalamic-pituitary-adrenal and -gonadal axes. The roles of the stress-related hormones corticotropin-releasing hormone (CRH) and glucocorticoids in normal and disease states are being examined, and clinical applications for these hormones and their antagonists are sought. We have demonstrated that several human states are characterized by hyperactivity or hypoactivity of the central stress system, which explains not only mood changes but also the propensity of patients with such disorders to develop cardiovascular or autoimmune complications. We are currently performing preclinical studies with a newly discovered nonpeptide, oral, CRH type 1 receptor antagonist, antalarmin, which show that such an antagonist may be useful in a large number of states characterized by hyperactivity of the stress system, such as depression, anorexia nervosa and idiopathic insomnia. At the level of the stress system target tissues, we have elucidated the molecular pathophysiology of glucocorticoid resistance by defining mutations and/or deletions of the glucocorticoid receptor gene leading to abnormally functioning or decreased receptors. In the same area,we have found abnormal expression of the beta dominant negative isoform of the glucocorticoid receptor in patients with glucocorticoid resistant asthma. Finally, we have determined that Vpr, a 15kD protein product of HIV-1, is a potent coactivator of the glucocorticoid receptor, causing marked target tissue glucocorticoid hypersensitivity, the presence of which may explain some of the clinical features and pathogenesis of AIDS.